6alpha-chloro-delta1, 4-androstadien-17beta-ol-3-one derivatives



United States Patent'Ofifice 3,080,391 Patented Mar. 5, 1963 The present invention relates to cyclopentanophen-anthrene compounds.

More particularly the present invention relates to novel steroidal 6ix-chloro-A -androstadien-17B-ol-3-one derivatives having a lower alkyl, lower alkenyl or lower alkinyl substituent at C-17 as well as to esters thereof. The novel compounds of the present invention just described and to be hereinafter described in detail are active progestational hormones. The present invention also relates to novel 6a-chloro-A -androsten-175-01-3-one derivatives having a 17a-lower alkenyl snbstituent. These last compounds are intermediates for the production of the corresponding l-dehydro compounds and are also progestational hormones.

In accordance with the present invention the novel A -derivatives were obtained by dehydrogenating the corresponding M-derivatives and the novel A -17a-lower alkenyl compounds were obtained by partial hydrogenation of the corresponding 17a-lower aikinyl compounds.

The novel compounds of the present invention are illustrated by the following formulas:

In the above formulas R represents hydrogen or a hydrocarbon carboxylic acyl group of up to 12 carbon atoms. This acyl group may be saturated or unsaturated of straight or branched chain, cyclic or mixed cyclicaliphatic and may be conventionally substituted as by methoxy, halogen etc. Typical acyl group are acetate, propionate, butyrate, hemisuccinate, enanthate, caproate, benzoate, trimethylacetate, phenoxyacetate, cyclopentyL propionate, phenylpropionate or B-chloropropionate. R represents a lower alkenyl group of up to 6 carbon atoms such as vinyl, propenyl, or butenyl. R represents a lower alkyl of up to 6 carbon atoms such as methyl, ethyl or propyl, or a lower alkenyl of up to 6 carbon atoms such as vinyl, propenyl or butenyl, or a lower alkinyl of up to 6 carbon atoms such as ethinyl, propinyl or butinyl.

The compounds above set forth are prepared by a process illustrated in the following equations:

0 R O R RQ partial I hydrogenation O:

In the above equations R, R and R represent the same groups as heretofore. R represents lower alkinyl of up to 6 carbon atoms such as ethinyl, propinyl or butinyl.

In practicing the process illustrated in the first equation a 17vc-1OW61' alkinyl-6a-chloro-testosterone compound was dissolved in an organic solvent and treated with hydrogen in the presence of a hydrogenation catalyst, preferably a palladium catalyst, until one mol of hydrogen was absorbed. The product compound was then conventionally separated and purified.

The dehydrogenation of the second equation may be carried out by microbiological methods known in steroid chemistry or by chemical means. Preferably the dehydrogenation was carried out by refluxing the starting com- .pounds with selenium dioxide in admixture with t-butanol, in the presence of a catalystic amount of pyridine for a long period of time. Upon conventional separation and purification there was obtained the corresponding ri -compounds.

The following specific examples serve to illustrate but are not intended to limit the present invention.

In the following specific examples the starting compounds of Examples IV to VIII were prepared in accordance with U.S. patent application Serial No. 776,694, filed November 28, 1958, now abandoned.

Example I A suspension of 750 mg. of 10% palladium on calcium carbonate catalyst in cc. of pure pyridine was stirred under an atmosphere of hydrogen for 2 hours at a temperature of 25 C. and at atmospheric pressure. There was then added 3 g. of 17a-ethinyl-6a-chloro-testosterone and the hydrogenation was continued under the same conditions until the equivalent of one mol of hydrogen had been absorbed. The catalyst was removed by filtration, washing the filter with a little pyridine, and the filtrate and washings were combined. The pyridine was removed under reduced pressure and the residue was crystallized from a mixture acetone-hexane. There was thus obtained 17a-vinyl-6e-chloro-testosterone.

3 Example 11 In the method of the previous example there was substituted for the 17a-ethinyl-6a-chloro-testosterone a C-17 ester of the latter, formed with a hydrocarbon carboxylic acid radical of up to 12 carbon atoms, thus giving rise to the formation of the corresponding 17-ester of 17aviny1-6m-chloro-testosterone. Specifically in this way there was prepared the acetate, propionate, cyclopentylpropionate and benzoate.

Example III Substituting-in, the methods of the previous examples, for the 17wethinyl-6a-chloro-testosterone or its ester, another 17a-alkinyl-6u-chloro-testosterone or an ester of the same, there Were obtained the corresponding l7ot-alkenyl- 6oz-chloro-testosterones or the esters of the same. For example, starting from l7a-butinyl-6a-chloro-testosterone there was prepared 17a-butenyl-6tt-chlorotestosterone, and from the propionate of 17 a-propinyl-6a-chlorotestosterone there was obtained the propionate of 17a-propeny1- 6a-chloro-testosterone.

Example IV A mixture of 2 g. of 17ot-methy1-6a-chloro-testosterone, 100 cc. of t-butanol, 0.8 g. of selenium dioxide and 0.5 cc. of pyridine was refluxed under an atmosphere of nitrogen .for 72 hours; the mixture was cooled, filtered throughcelite, washing the filter with hot t-butanol, and the combined filtrate and washings was evaporated to dryness under reduced pressure. The residue was dissolved in acetone, treated .with decolorizingcharcoa-l and the solution Wasdried over anhydrous sodium sulfate and evaporated to dryness. Chromatographic purification of the residue on neutral alumina yielded 17a-methyl-6achloro-A -androstadien-l7fl-ol-3-one.

Example V By the method of the previous example, 17a-ethinyl- 6ct-chloro-testosterone was converted into 17a-ethinyl- 6a-chloro-A androstadien-17fi-o1-3-one.

Example VI By the method of Example IV, l7a-vinyl-6a-chlorotestosterone was converted into l7a-vinyl-6a-chloro-A androstadien-17fi-ol-3-one.

Example VII Following the method of Example III there were also prepared from the corresponding A -compounds other free Hot-lower alltyl, l'lcc-IOWGI alkenyl and 170t-lOWel alkinyl derivatives of 6a-chloro testosterone as well as the corresponding esters of hydrocarbon carboxylic acids of up to 12 carbon atoms. These included specifically the acetate, propionate, cyclopentylpropionate and benzoate of 17OL-I'i'13lhy1, ethyl, propyl, vinyl, propenyl, butenyl, ethinyl propinyl and butinyl derivatives of 6achloro-A -androstadien-17fi-ol-3-one and the free compounds.

We claim:

1. oa-chloro-flwlower alkenyl-N -androstadien-17 8- 01-3-one.

2. The hydrocarbon carboxylic acid esters of up to 12 carbonatoms of 6OL-Ch1OI'O-170l-1OWCI' alkenyl-A -androstadien-17B-ol-3-one.

References Cited in the file of this patent UNITED STATES PATENTS 2,085,474 Ruzicka June 29, 1937 2,837,464 Nobile June 3, 1958 2,838,490 Babcock et a1. June 10, 1958 2,838,500 Campbell et al -June 10, 1958 

1. 6A-CHLORO-17A-LOWER ALKENYL-$1,4-ANDROSTADIEN-17 BOL-3-ONE. 